The ability to administer biologically effective drugs that are poorly soluble in biocompatible solvents to mammals has been a major hurdle in the realm of pharmaceutical and medicinal chemistry. In particular, difficulties arise when an active drug is either insoluble in water or unstable in other biocompatible solvents.
One way to solubilize medicinal agents is to chemically modify them or conjugate them to another molecule to alter the solubility profile in a particular solvent. Conjugates of active drugs, often referred to as prodrugs, include chemical derivatives of biologically-active parent compounds that are converted into the parent compounds in vivo. The release of the active parent drug from the prodrug conjugate may occur as the result of processes such as hydrolysis or enzymatic cleavage. The rate of release is influenced by several factors, including the type of chemical bond joining the active parent drug to the conjugate moiety.
Incorporating a water-soluble moiety (e.g., polyethylene glycol, polyglutamate, or polymer) to increase solubility and circulation life of a drug has been investigated by others. The use of fatty acids to conjugate to active drugs for purposes of tumor targeting has also been investigated as a means of improving therapeutic index.
Many potent drugs, such as camptothecin and its analogues (e.g., 10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecin), taxanes (e.g., paclitaxel, docetaxel), candesartan, amphotericin B, azathioprine, cyclosporine, entacapone, danazol, eletriptan, and bosentan, to name a few, are poorly soluble or have poor cell permeability. Solubility problems of potential therapeutic agents are common and often cause delays in drug development. Several technologies have been developed to facilitate the delivery of poorly soluble and insoluble compounds to patients. Examples of technologies specifically designed to solve solubility problems include complexing agents, nanoparticles, microemulsions, solubility enhancing formulations, prodrugs, and novel polymer systems.
Paclitaxel (see structure below), a natural product found in the inner bark of the Pacific Yew tree, is an example of an important chemotherapeutic agent with wide spectrum of activity against solid tumors, primarily breast, ovarian, colon and non-small cell lung cancer.

Paclitaxel exerts its antitumor activity by binding to tubulin and stabilizing microtubules and thus blocking cell mitosis. However, paclitaxel, like many other potent biologically active molecules, has very limited aqueous solubility.
Camptothecin (CPT) (see structure below) is another example of a poorly soluble and difficult to formulate anti-cancer drug.

CPT is a quinoline-based alkaloid found in the bark of the Chinese camptotheca tree and the Asian nothapodytes tree. CPT includes four planar rings (ABCD) and one boat conformational ring (E). CPT has been found to have a broad spectrum of antitumor activity, especially in human solid tumors. However, the lactone (ring E) of camptothecin and its derivatives is quite labile in alkaline condition and physiological pH. The opening of this ring to form an acid salt or carboxylate species results in significant loss of anticancer activities. Efforts have been made since the early 1960s, when CPT was discovered by Wall and Wani, to improve upon the anti-cancer activities formulation of camptothecin has been developed to date because of its poor solubility in both water and organic solvents. However, water-soluble analogues of camptothecin, irinotecan hydrochloride (CAMPTOSAR) and topotecan hydrochloride (HYCAMPTIN), have been developed and are the only camptothecin analogs currently approved by the Food and Drug Administration.
Recently, a vitamin E (α-tocopherol)-based emulsion formulation technology for paclitaxel drug delivery has been developed. In the formulation, paclitaxel is solubilized in α-tocopherol and formulated as an oil-in-water emulsion. However, while paclitaxel is soluble in α-tocopherol, the solubility of other active moieties (including camptothecin and other taxanes) in α-tocopherol is limited. Therefore, there continues to be a need for new methods, which are both safe and efficacious, of solubilizing and delivering poorly soluble active drug molecules.